获得性耐药性对骨肉瘤治疗提出了重大挑战。因此，我们有必要发现和开发替代的抗癌策略。先前的研究表明，二十碳五烯酸（EPA）可显着增加癌细胞的化疗敏感性。在这项研究中，我们发现EPA增强了骨肉瘤对顺铂（DDP）的敏感性。有趣的是，除了抑制生长和诱导细胞凋亡之外，EPA 还可以增强 DDP 诱导的铁死亡。 Western blot 分析证实，EPA 处理显着降低细胞中 DNA 依赖性蛋白激酶催化亚基 (DNA-PKcs)、p-AKT、核因子红细胞 2 相关因子 2 (NRF2) 和谷胱甘肽过氧化物酶 4 (GPX4) 的表达。 siRNA 敲低 DNA-PKcs 进一步增强 EPA 诱导的铁死亡水平。重要的是，EPA 可以逆转 DDP 诱导的程序性死亡配体 1 (PD-L1) 的高表达水平。 ELISA 和蛋白质印迹分析显示，EPA 处理降低了 IL-6 和 p-STAT3 的水平，而 DDP 处理则增加了 IL-6 和 p-STAT3 的水平。此外，免疫共沉淀 (co-IP) 测定证实了 DNA-PKcs 和 PD-L1 之间的相互作用，并且 DNA-PKcs 的敲低进一步降低了 PD-L1 的表达。该数据提供了第一个证据，表明EPA抑制DNA-PKcs/AKT/NRF2/GPX4途径以增强铁死亡，并抑制IL-6/STAT3和DNA-PKcs以减少PD-L1表达，从而使骨肉瘤对DDP敏感。 EPA 和 DDP 的结合提出了一种令人鼓舞且有前途的抗肿瘤策略。版权所有 © 2023。由 Elsevier B.V. 出版。

Acquired drug resistance poses a significant challenge in osteosarcoma therapy. Therefore, it is necessary for us to discover and develop an alternative anti-cancer strategy. Previous studies have shown that eicosapentaenoic acid (EPA) significantly increases chemosensitivity in cancer cells. In this study, we discovered that EPA enhances the sensitivity of osteosarcoma to cisplatin (DDP). Interestingly, in addition to inhibiting growth and inducing apoptosis, EPA also enhances DDP-induced ferroptosis. Western blot analysis confirmed that EPA treatment significantly decreases the expression of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), p-AKT, nuclear factor erythroid 2-related factor 2 (NRF2), and glutathione peroxidase 4 (GPX4) in cells. Knockdown of DNA-PKcs by siRNA further enhances the level of ferroptosis induced by EPA. Importantly, EPA can reverse the high expression level of programmed death ligand 1 (PD-L1) induced by DDP. ELISA and western blotting analysis revealed that EPA treatment decreases the levels of IL-6 and p-STAT3, which are increased by DDP treatment. Furthermore, a co-immunoprecipitation (co-IP) assay confirmed the interaction between DNA-PKcs and PD-L1, and knockdown of DNA-PKcs further reduces the expression of PD-L1. This data provides the first evidence that EPA suppresses the DNA-PKcs/AKT/NRF2/GPX4 pathway to enhance ferroptosis, and inhibits IL-6/STAT3 and DNA-PKcs to decrease PD-L1 expression, thereby sensitizing osteosarcoma to DDP. The combination of EPA and DDP presents an encouraging and promising anti-tumor strategy.Copyright © 2023. Published by Elsevier B.V.